Muscular Dystrophy (MD) is a group of 30+ diseases that causes progressive weakness and loss of muscle mass due to mutations in dystrophin, a protein needed to form healthy muscle. Duchenne MD (DMD) comprises half of MD; affects 1 in 3,500 boys and ⅓ have no family history. Onset is between ages 2 and 3 and progresses rapidly. Becker MD (BMD) is the 2nd most common form of MD; 1 in 30,000 boys; BMD is milder and slowly progresses compared to DMD; symptoms may not be seen until teens, mid-20s or later. Limb-Girdle MD (LGMD) can affects as many as 1 in 14,500 and causes weakness and wasting of the muscles in the proximal arms and legs.
Complications of muscular dystrophy include inability to walk, breathing problems, scoliosis, cardiomyopathy and swallowing problems. There is no cure. Treatment to-date is to manage symptoms or slow progression.
Delta-sarcoglycan (DSG) is a transmembrane glycoprotein which forms as a complex, the dystrophin-associated glycoprotein complex (DGC). The DGC plays a central role in maintaining integrity of the cell membrane by linking the extracellular matrix (“ECM”; a substance containing collagen, elastin, proteoglycans, glycosaminoglycans, and fluid, produced by cells and in which the cells are embedded) and cytoskeleton (the inner structural elements, or backbone, of a cell. It consists of microtubules and various filaments that spread out through the cytoplasm, providing both structural support and a means of transport within the cell).
In both skeletal and cardiac muscle, the DGC consists of dystrophin, the syntrophins, a- and b-dystroglycan (a-, b-DG), the sarcoglycans (a-, b-, g-, d-SG), and sarcospan (SSPN).
Mutations in the dystrophin gene lead to high incidence of cardiomyopathy in DMD and BMD. Mutations in sarcoglycans within DGC are responsible for Limb-Girdle MD and associated with cardiomyopathy. A major function of dystrophin is to strengthen the sarcolemma by cross-linking the ECM with the cytoskeleton. Utrophin and a7b1 integrin fulfil the same function. Dystrophin works to connect sarcolemma to cytoplasmic actin cytoskeleton. Dysfunction produces membrane instability, elevated [Ca2+]I and disrupted NO signaling. γ- and δ-SG form a core necessary for delivery/retention of other SG to the membrane.
Patients with mutations in DSG (e.g., patients suffering from muscular dystrophy) present with cardiomyopathy.
Absence of dystrophin in Duchenne muscular dystrophy (DMD) causes progressive breakdown of muscle cells. In the heart, loss of dystrophin leads to abnormally increased intracellular calcium, degradation of contractile proteins, fibrosis, and myocardial death. With advances in respiratory support, cardiomyopathy is now a primary cause of death amongst DMD patients. DM D patients develop an insidious decline in cardiac function leading to heart failure and can also develop arrhythmias, with the potential for sudden cardiac death, even with minimal decrease in cardiac function by physical symptoms or echocardiography. Because of this, cardiac magnetic resonance (CMR) is useful for detection of early cardiac involvement in DMD patients. Increased myocardial fibrosis and expanded extracellular volume in CMR predicts left ventricular (LV) dysfunction, and are associated with an increased risk of arrhythmia and hospitalization for heart failure or death.
While less severely affected than skeletal and cardiac muscle, intestinal smooth muscle function can also be altered by atrophy and fibrosis. In DMD patients, particularly when wheelchair-bound, this can lead to poor gut motility, gastroesophageal reflux, and chronic constipation, which negatively affect patient quality of life. More critically, the possible complications of dilatation, fecal impaction, or intestinal pseudo-obstruction can be life-threatening.
The cellular damage characteristic of DMD is also associated with increased formation of reactive oxygen species, or oxidative stress. (Grosso, et al., Isoprostanes in dystrophinopathy: Evidence of increased oxidative stress. Brain Dev. 2008; 30(6):391-5. doi:10.1016/j.braindev.2007.11.005. PubMed PMID: 18180123). These free radicals can react with membrane phospholipids to form isoprostanes, which circulate freely after release by phospholipase, and the relatively stable 15-F2t-isoprostane (F2-IsoP) is a primary biomarker of in vivo oxidative stress. (Montuschi, et al., Isoprostanes: markers and mediators of oxidative stress. FASEB J. 2004; 18(15):1791-800. doi: 10.1096/fj.04-2330rev). Plasma F2-IsoP levels are increased in DMD patients (Grosso, et al., cited above), and urinary F2-IsoP levels are increased in heart failure patients, where they correlate with the severity of the disease (Cracowski, et al., Increased formation of F(2)-isoprostanes in patients with severe heart failure. Heart. 2000; 84(4):439-40. PubMed PMID:10995421; PMCID: PMC172944614). In addition to heralding cellular stress, isoprostanes can also be the source of damage via activation of the thromboxane/prostanoid receptor (TPr), and F2-IsoP signaling through the TPr decreases angiogenesis and causes vasoconstriction (Bauer, et al., Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation. Brit J Pharmacol. 2014; 171:3115-3115) and fibrosis (Acquaviva, et al. Signaling pathways involved in isoprostane-mediated fibrogenic effects in rat hepatic stellate cells. Free Radic Biol Med. 2013; 65:201-7, doi: 10.1016/j.freeradbiomed.2013.06.023. PubMed PMID: 23792773; Comporti, et al. Isoprostanes and hepatic fibrosis, Mol Aspects Med. 2008; 29(1-2):43-9. doi: 10.1016/j.mam.2007.09.011. PubMed PMID: 18061254).
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This can be a reactive, benign, or pathological state, and physiologically acts to deposit connective tissue, which can obliterate the architecture and function of the underlying organ or tissue. Fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing. While the formation of fibrous tissue is normal, and fibrous tissue is a normal constituent of organs or tissues in the body, scarring caused by a fibrotic condition may obliterate the architecture of the underlying organ or tissue.
To date, there are no commercially available therapies that are effective in treating or preventing fibrotic disease. Conventional treatment frequently involves corticosteroids, such as prednisone, and/or other medications that help improve muscle strength and delay the progression of certain types of muscular dystrophy. Also, heart medications, such as angiotensin-converting enzyme (ACE) inhibitors or beta blockers may be administered to muscular dystrophy patients, if the muscular dystrophy damages the heart.